RARE DISEASE
Large granular lymphocyte leukemia
Large granular lymphocyte leukemia
Large granular lymphocyte leukemia
Drug discovery
2
drugs
With orphan designations
Overview
Large granular lymphocyte leukemia (LGLL) is a rare chronic lymphoproliferative disorder of cytotoxic T or NK cells, characterized by clonal expansion of large granular lymphocytes (>6 months), cytopenias (neutropenia, anemia), and autoimmune associations like rheumatoid arthritis. Diagnosis requires peripheral blood analysis, flow cytometry (CD3±/CD8+/CD57+), and T-cell receptor clonality testing. Management relies on immunosuppressive therapy, with indolent progression but morbidity linked to infections and transfusion dependence [1][2][6][14].
Burden
Median survival: ~9 years (reduced vs general population), with mortality driven by infections from neutropenia [2][11][15]
Chronic management: 45% require systemic therapy at diagnosis; frequent relapses necessitate long-term immunosuppression [2][6][12]
Economic impact: Costs from recurrent hospitalizations, transfusions, and biologic therapies for cytopenias/autoimmunity [9][14]
Therapies
First-line: Methotrexate (10 mg/m² weekly) for neutropenia; cyclophosphamide (50-100 mg/day) or cyclosporine (3 mg/kg/day) for anemia [3][6][12][16]
Refractory disease: Purine analogs (fludarabine), alemtuzumab, or splenectomy [6][12][18]
Supportive care: G-CSF for severe neutropenia; indefinite maintenance therapy often required [8][16]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
309 drug discovery papers about Large granular lymphocyte leukemia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
309 drug discovery papers about Large granular lymphocyte leukemia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-28 | Clinical Manifestations and Genetic Profile of Chinese Patients with NK-Cell Large Granular Lymphocytic Leukemia-A Single-Center Retrospective Analysis.
Natural killer cell large granular lymphocytic leukemia (NK-LGLL) is a rare and heterogenous lymphoproliferative disorder. This study retrospectively evaluated 35 consecutive Chinese patients (median age 58 years) to evaluate their unique clinical-biological profiles and treatment responses. Our Chinese population exhibited a distinct comorbidity spectrum, characterized by a lower prevalence of concurrent arthritis (2.9%) and secondary malignancies, compared with Western cohorts. At diagnosis, 31.4% of the cohort had neutropenia, 42.9% had anemia, and 31.4% had thrombocytopenia. The median large granular lymphocyte count was 3.9 × 109/L (range 0.11-114.8 × 109/L; IQR 1.9 × 109/L, 5.9 × 109/L). Immunophenotyping consistently identified as a CD3- CD56+ clone. Notably, genomic profiling via NGS revealed a STAT3 mutation rate of 14.3%. Regarding therapeutic efficacy, frontline immunosuppressive therapy with cyclophosphamide or cyclosporine was associated with favorable clinical responses (best overall response, complete remission rate 66.7% for both). Additionally, sirolimus emerged as a potentially highly effective salvage option, yielding an overall response rate of 85.7% (95%CI 42.1-99.6%) and complete remission rate of 57.1%. With an estimated 3-year overall survival rate of 85.6% (95%CI 73.3%, 99.8%), our findings suggest a generally indolent clinical course of NK-LGLL in this Chinese cohort and highlight the potential of mTOR inhibition in refractory cases, warranting further prospective investigation.
2026-07-23 | [Sustained complete remission achieved with tofacitinib in a refractory T-cell large granular lymphocytic leukemia].
Treatment of large granular lymphocytic leukemia, particularly T-cell leukemia (LGL-T), remains challenging. JAK inhibitors, although still scarcely evaluated, appear promising. An 85-year-old woman was treated for a refractory LGL-T associated with neutropenia, unclassified polyarthritis and vitiligo. During the 7-year course of the disease, she received alternatively cyclosporine, cyclophosphamide and methotrexate, associated with prednisone and/or filgrastim. During a severe relapse with agranulocytosis complicated by infectious pneumonia, no response was observed after 14 days of filgrastim. Ten days after initiation of tofacitinib, a marked increase of the neutrophil count (98G/L) occurred, associated with Sweet syndrome. Both resolved rapidly with filgrastim discontinuation. Tofacitinib allowed a rapid and complete remission of both hematological and clinical manifestations, which was maintained throughout 37 months of follow-up. This report adds to the limited evidence supporting tofacitinib in LGL-T and further highlights the potential of JAK-inhibition, particularly in refractory and systemic forms.
2026-06-06 | T-cell large granular lymphocyte leukaemia with pure red cell aplasia harbouring a somatic STAT3 P715L mutation.
T-cell large granular lymphocyte leukaemia (T-LGLL) is a chronic lymphoproliferative disorder often associated with pure red cell aplasia (PRCA). We report a unique case of a woman in her 50s presenting with PRCA secondary to T-LGLL, in which targeted next-generation sequencing identified a somatic STAT3 P715L mutation. This variant, previously described only in germline mutation in STAT3 gain-of-function syndrome, has not been reported as a somatic mutation in T-LGLL. Immunohistochemical analysis revealed constitutive STAT3 (signal transducer and activator of transcription 3) activation in clonal CD8+ T cells, suggesting a pathogenic role for the P715L mutation. The patient responded to ciclosporin therapy with gradual haematological improvement and became transfusion-independent within 6 months. This case highlights the importance of molecular profiling in T-LGLL presentations and expands the known mutational spectrum of STAT3 It also raises the possibility that non-SH2 (Src homology 2) domain STAT3 mutations may contribute to disease pathogenesis and influence treatment response in T-LGLL.
2026-04-29 | Molecular Biological Insights into Large Granular Lymphocyte Leukemia
Large granular lymphocytic leukemia (LGLL) represents a rare, indolent T-cell lymphoproliferative disorder. Clinically, it frequently manifests as cytopenia and organ infiltration. First-line immunosuppressive therapy induces clinical remission in approximately one-third to one-half of patients. Nevertheless, a significant proportion of patients experience a chronic disease course, necessitating long-term disease management. Precision medicine emerges as the pivotal future direction for this disease, with advances in molecular biology serving as the most potent driving force. In recent years, facilitated by the widespread adoption of next-generation sequencing technologies, the diagnostic and prognostic significance of gene mutations – such as those in STAT3 and STAT5B – has become increasingly elucidated within LGLL. These discoveries concurrently provide a rational foundation for exploring targeted therapeutic approaches, notably JAK inhibitors. However, the molecular landscape of LGLL remains substantially uncharted territory, warranting dedicated research efforts. This review synthesizes current progress in the molecular biology of LGLL, aiming to stimulate further investigation and offer insights for researchers in the field.
2026-03-03 | P066 | <i>STAT3</i>-mediated circular RNAs dysregulation in neutropenic T-large granular lymphocyte leukemia patients
Introduction. T-Large Granular Lymphocyte Leukemia (T-LGLL) is a rare chronic lymphoproliferative disorder with unclear pathogenesis. Clonal expansion is driven by pro-inflammatory cytokines that induce JAK/STAT stimulation. Activating STAT mutations have been identified, with STAT3 lesions being typical of CD8+ T-LGLL and distinguishing symptomatic cases, mainly for neutropenia, from indolent ones. The discovery of the STAT3-miR-146b-FasL axis in STAT3-mutated CD8+ cases has highlighted the role of non-coding RNAs (ncRNAs). This study aims to clarify the role of circular RNAs (circRNAs), a class of ncRNAs, whose involvement in T-LGLL remains unexplored.Methods. We considered RNA-sequencing (RNA-seq) data (GEO GSE228868) of 20 T-LGLL cases and 5 healthy donors (HD). CircRNA identification and analysis was carried out using the CircCompara2/edgeR pipeline. Candidate circRNAs were validated in an independent cohort (n=26) through Sanger sequencing and RT-qPCR. Patient cells were treated with IL-6 (20 ng/μL) or the STAT3 inhibitor STATTIC (ST) (3.5 μM). After 24 hours cell viability, STAT3 activation, and circRNA expression were assessed via Annexin V staining, western blot, and RT-qPCR, respectively.Results. A total of 5,948 circRNAs (p-adj<0.05) were detected through RNA-seq. Principal component analysis revealed distinct circRNA expression patterns between T-LGLL patients and HD, with 358 circRNAs differentially expressed in neutropenic STAT3-mutated patients compared to asymptomatic ones. The altered expression of 11 circRNAs was validated in an independent cohort. Of these, 5 were specifically altered in STAT3-mutated CD8+ patients: 4 were up-regulated, while circZC3H12B was down-regulated. Among upregulated circRNAs, circPVT1 and circZBTB46 were previously associated with oncogenic roles in different malignancies, whereas circZC3H12B, previously known as circX, was found highly expressed in normal lymphocytes and downexpressed in Acute Lymphoblastic Leukemia. To assess the potential link between STAT3 activation and circRNA dysregulation, cells from asymptomatic patients were stimulated ex vivo with IL-6 which is known to trigger STAT3. Protein activation, confirmed by western blot (p<0.01), modulated the 5 circRNAs to levels comparable to symptomatic cases. Consistently, experiments on cells from symptomatic patients with STAT3 hyperactivating variants treated with ST, an inhibitor of STAT3 phosphorylation (p<0.05), showed an inverse modulation of circRNAs expression compared to IL-6 treatment.Conclusions. This study reveals a T-LGLL-specific circRNA signature. neutropenic CD8+ STAT3-mutated patients showed a proper distinct circRNA profile, suggesting a role of these transcripts in disease severity and clinical manifestation. Experiments demonstrated that STAT3 activation drives circRNA dysregulation, offering new insights into T-LGLL pathogenesis. Future studies will explore circRNA function through siRNA silencing and RNA pull-down assays.
cell therapies
2026-06-23 | Auer Rod-Like Inclusions in T-cell Large Granular Lymphocytic Leukaemia.
A 71-year-old man presented with cytopenias and splenomegaly. Diagnostic workup revealed T-cell large granular lymphocytic leukemia (T-LGLL), characterized by a clonal CD8+ T-cell population with STAT3 mutation. A rare morphological finding of myeloperoxidase-negative Auer rod-like inclusions in the leukemic lymphocytes was observed, a feature seldom reported in this T-cell malignancy.
2026-05-20 | NK-large Granular Lymphocytic Leukemia
This chapter outlines the key immunophenotypic features of NK-large granular lymphocytic leukemia (NK-LGLL) and highlights the use of NK-cell receptor patterns, analyzed through flow cytometry, to establish NK-cell clonality. It also emphasizes the essential differences between NK-LGLL and its mimics, such as reactive NK-cell proliferation, NK-cell clones of uncertain significance, and aggressive NK-cell leukemia.
2026-04-17 | [A single-center study on the clinical characteristics of 15 cases of large granular lymphocytic leukemia].
This study retrospectively analyzed the clinical data of 15 patients diagnosed with large granular lymphocytic leukemia (LGLL) at the First Affiliated Hospital of Chongqing Medical University between January 2017 and December 2024. The median age was 50 years, and the main clinical manifestations included fatigue (73.3%), splenomegaly (46.7%), and lymphadenopathy (33.3%). None of the patients had autoimmune diseases. Laboratory examinations primarily demonstrated decreased hemoglobin levels (100%) and/or neutropenia (73.3%). The bone marrow smears showed an increase in lymphocyte proportion, and pure red cell aplasia was frequently observed. The typical immunophenotype was TCRαβ(+)TCRγδ(-)CD3(+)CD4(-)CD8(+)CD16(-)CD10(-)CD30(-)CD45RA(+)CD45RO(-)CD56(-)CD25(-), with monoclonal T-cell proliferation confirmed in all patients. Further, 8 patients demonstrated decreased complement C3 or C4 levels. The overall response rate of first-line immunosuppressive therapy for patients with LGLL was 85.7% (12/14) .
2026-03-31 | Central Nervous System Involvement as an Initial Manifestation of T-Cell Large Granular Lymphocyte Leukemia
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2026-02-10 | [The value of T-cell receptor gene rearrangement in the auxiliary diagnosis of T-cell large granular lymphocytic leukemia].
Objective: To explore the characteristics and auxiliary diagnostic value of T-cell receptor (TCR) gene rearrangement in T-cell abnormal clonal diseases, including T-cell large granular lymphocytic leukemia (T-LGLL) . Methods: Altogether, 103 newly diagnosed patients with T-LGLL, 18 with aplastic anemia (AA), 3 with pure red cell aplasia, 111 with systemic lupus erythematosus (SLE), and 30 healthy controls admitted at Jiangsu Province Hospital from September 2011 to November 2023 were enrolled. TCR gene rearrangement was detected by polymerase chain reaction and capillary electrophoresis, and TCRβ chain variable region (TCRVβ) subfamily and TCRβ chain constant region 1 (TRBC1) were detected by flow cytometry. The auxiliary diagnostic value of these three detection methods for T-LGLL was compared. Meanwhile, Sanger sequencing was used to detect STAT3 gene mutations in T-LGLL patients, and the mutation characteristics and clinical features of these patients were analyzed. Results: In T-LGLL patients, 57 were men and 46 were women, and the patients' median age was 61 (28-81) years. Altogether, 97.1% (100/103) of the patients were positive for TCR gene rearrangement, and TCRβ gene rearrangement showed the highest incidence (95.1%, 98/103). TCRβ gene rearrangements were further classified into TCRβ (V-J) (42.9%, 42/98), TCRβ (D-J) (15.3%, 15/98), and copositive for two TCRβ gene rearrangements (41.8%, 41/98). This was followed by TCRγ (47.6%, 49/103) and TCRδ (4.9%, 5/103) gene rearrangements. The detection rates of TCRVβ and TRBC1 were 89.5% (51/57) and 73.5% (25/34), respectively. The detection rate of TRBC1 was significantly lower than that of TCR gene rearrangement (P=0.004). The detection rates of TCR gene rearrangement in the AA, SLE, and healthy control groups were 19.0%, 6.3%, and 3.3%, respectively. Compared with healthy controls and SLE patients, the T-LGLL patients had significantly lower HGB, RBC, and ANC but significantly higher absolute lymphocyte count (ALC) (all P<0.01). Compared with the AA group, the white blood cell count, ALC, and platelet counts of the T-LGLL patients were significantly higher (all P<0.001). Compared with the AA, SLE, and healthy control groups, the T-LGLL patients were older and had a significantly higher detection rate of TCR gene rearrangement (all P<0.05). Within the T-LGLL cohort, patients with positive TCRβ (D-J) gene rearrangement had significantly lower incidence of autoimmune diseases (3.6% vs 19.1%, P=0.011) and HGB of ≥100 g/L (33.9%vs 63.8%, P=0.002), but a significantly higher incidence of B symptoms (64.3% vs 38.3%, P=0.009), than those patients without this rearrangement. Meanwhile, patients with positive TCRγ gene rearrangement had significantly higher incidence of STAT3 gene mutations (58.3% vs 30.2%, P=0.012). The median follow-up time and overall survival (OS) rate of T-LGLL patients were 43 (3-178) months and 95.1% (98/103), respectively. No significant difference in the OS was observed among the patients with different types of TCR gene clonal rearrangements (all P>0.05) . Conclusion: The detection rate of TCR gene rearrangement for T-cell clones is higher than that of TCRVβ and TRBC1. Patients with positive TCRβ (D-J) gene rearrangement have a higher incidence of B symptoms, lower incidence of autoimmune diseases, and lower HGB levels. Patients with positive TCRγ gene rearrangement are more likely to develop STAT3 gene mutation. These characteristics may be helpful in the differential diagnosis of T-LGLL.
proteins
2026-06-17 | Observation of Hematologic Improvement with Luspatercept in Patients with Anemia from Diverse Hematologic Disorders: A Single-Center Retrospective Clinical Analysis
Background: Anemia is a common clinical condition in hematology, associated with diverse etiologies and treatment strategies, many of which have notable limitations. Luspatercept, a novel erythroid maturation agent, has shown promise in treating anemia, particularly in patients with β-thalassemia and myelodysplastic syndromes (MDS). This study aimed to evaluate the real-world hematologic effectiveness of luspatercept across various anemia subtypes. Materials and Methods: A retrospective observational study was conducted on 22 patients with anemia of different origins—MDS, post-hematopoietic stem cell transplantation (HSCT), aplastic anemia (AA), and T-cell large granular lymphocytic leukemia (T-LGLL)—who received luspatercept therapy at the 960th Hospital from June 2023 to January 2025. Hematologic improvement was assessed using the International Working Group (IWG) 2018 criteria for erythroid response (HI-E). Pre- and post-treatment changes in hemoglobin (Hb), reticulocyte percentage (RET %), and absolute reticulocyte count (RET #) were analyzed using the Wilcoxon Signed-Rank Test. Multivariate regression was employed to control for age, gender, and disease severity. Statistical significance was set at P ≤ 0.05, and all analyses were performed using SPSS version 27.0. Results: Among the 22 patients, 10 (45.5%) had MDS (5 low-risk, 5 intermediate-to-high-risk), 6 (27.3%) post-HSCT anemia, 4 (18.2%) AA, and 2 (9%) T-LGLL. A total of 16 patients (72.7%) achieved a clinically meaningful erythroid response. Seven (43.8%) of these remained transfusion-independent until the last follow-up, with a median duration of 19.5 weeks (range: 8.6–47). Median time to initial response was 3.86 weeks (range: 0.57–25.57). Significant increases were observed in Hb (P < 0.001) and RET # (P = 0.001), while the increase in RET % did not reach statistical significance (P = 0.088). These findings support the efficacy of luspatercept in promoting erythropoiesis and improving anemia in a heterogeneous patient population. Conclusion: Luspatercept demonstrated significant hematologic improvement, particularly in hemoglobin levels, in patients with anemia from various hematologic disorders. These results support its broader therapeutic potential. Future multicenter, prospective studies are warranted to validate its role in treating other forms of anemia.
2023-10-23 | Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia.
T-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes that can result in severe neutropenia, anemia, and bone marrow failure. Strong evidence from patients and mouse models demonstrate the critical role of interleukin-15 (IL-15) in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other γc cytokines to their cellular receptor complex, which has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in preclinical studies. We conducted a phase 1/2 trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) and required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based on response criteria from the Eastern Cooperative Oncology Group 5998 T-LGLL trial. BNZ-1 demonstrated clinical partial responses in 20% of patients with T-LGLL with minimal toxicity and the maximum tolerated dose was not reached. Furthermore, T-LGL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day 2, including in clinical nonresponders, with changes that remained statistically different from baseline throughout treatment (P < .005). We report first-in-human proof that T-LGL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in patients with T-LGLL shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. This trial was registered at www.clinicaltrials.gov as #NCT03239392.
2019-08-14 | [Successful treatment of pure red cell aplasia with cyclosporin in a patient with T-cell large granular lymphocytic leukemia harboring the STAT3 D661V mutation].
T-cell large granular lymphocyte (T-LGL) leukemia is a chronic T-cell monoclonal disease that is occasionally associated with pure red cell aplasia (PRCA). A 71-year-old previously healthy man complained of physical fatigue and exhibited anemia (hemoglobin, 10.5 g/dl) with lymphocytosis (76%) showing LGL. The LGL cells expressed CD3, CD7, CD8, and T-cell receptor (TCR) -α/β. TCR-β/γ gene rearrangement was positive. He was thus diagnosed with CD8＋ T-LGL leukemia. Anemia progressed with low reticulocyte count (0.11%), and the patient became blood transfusion-dependent, but no distinct abnormality caused the anemia. Bone marrow aspiration revealed an increase in lymphocytes (33.6%) and a decrease in erythroblasts (M/E ratio, 6.1). He was thus diagnosed with T-LGL-associated PRCA. Oral cyclosporin A administration resulted in prompt improvement of anemia, suggesting its high sensitivity. Whole-exome sequencing of his peripheral blood DNA revealed somatic mutations in 33 genes, including the STAT3 gene, implying their roles in T-LGL leukemia.
2018-10-23 | IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability
Interleukin-15 (IL-15) and IL-2 drive T-cell malignancies including T-cell large granular lymphocyte leukemia (T-LGLL) and HTLV-1 driven adult T-cell leukemia (ATL). Both cytokines share common γ-chain receptors and downstream signaling pathways. T-LGLL is characterized by clonal expansion of cytotoxic T cells and is associated with abnormal JAK/STAT signaling. ATL is an aggressive CD4+ T-cell neoplasm associated with HTLV-1. T-LGLL and ATL share dependence on IL-2 and IL-15 for survival and both diseases lack effective therapies. BNZ-1 is a pegylated peptide designed to specifically bind the γc receptor to selectively block IL-2, IL-15, and IL-9 signaling. We hypothesized that treatment with BNZ-1 would reduce cytokine-mediated proliferation and viability. Our results demonstrated that in vitro treatment of a T-LGLL cell line and ex vivo treatment of T-LGLL patient cells with BNZ-1 inhibited cytokine-mediated viability. Furthermore, BNZ-1 blocked downstream signaling and increased apoptosis. These results were mirrored in an ATL cell line and in ex vivo ATL patient cells. Lastly, BNZ-1 drastically reduced leukemic burden in an IL-15-driven human ATL mouse xenograft model. Thus, BNZ-1 shows great promise as a novel therapy for T-LGLL, ATL, and other IL-2 or IL-15 driven hematopoietic malignancies.
2016-01-01 | The case of T-cell large granular lyphocyte leukemia presented as transfusion dependent anemia with sustained response to cyclosporine a therapy: Case report
Case report. A 41-year-old man presented with anemia, lymphocytosis and splenomegaly. T-cell large granular lymphocyte leukemia was diagnosed based on lymphocytosis of T-cell large granular lymphocytes, characteristic immunophenotype (CD3+, CD8+, CD16+, CD57+) of the lymphocytes and clonally rearranged T-cell receptor genes. Therapy indication was transfusion-dependent anemia. Initial cyclosporine therapy and low-dose oral methotrexate failed to control anemia and lymphocytosis. Yet, a complete clinical and hematological response (without molecular remission) was achieved and sustained when cyclosporine was reintroduced into the therapy. Conclusion. Our case confirms that cyclosporine therapy is effective in treating T-cell large granular lymphocyte leukemia and suggests that indefinite treatment may not be needed to maintain the response.
antibodies
2026-08-06 | Multilineage lymphoid clonal hematopoiesis: a cross-sectional, correlative analysis of plasma cell dyscrasias and large granular lymphocytic leukemia.
Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.
2026-01-03 | Mutational Spectrum of T-Cell Large Granular Lymphocytic Leukemia: Insights From the AACR Project GENIE Consortium.
T-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder of cytotoxic T cells in the peripheral blood, bone marrow, and spleen. This analysis was conducted to characterize genomic alterations and highlight potential therapeutic targets, with the goal of refining the molecular landscape of T-LGLL by emphasizing population-specific biomarkers. This study utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to identify common gene mutations. Using the AACR GENIE database, a retrospective analysis of T-cell large granular lymphocyte leukemia (T-LGLL) samples was performed. The data was evaluated by extracting patient demographics and excluding synonymous mutations from consideration. Statistical significance was assessed using chi-squared tests and computational analyses in RStudio (R Foundation for Statistical Computing, Boston, MA, USA). Somatic mutations and chromosomal copy number variations were evaluated, with statistical significance defined as p=0.001. Frequently observed somatic mutations included STAT3 (41.7%), STAT2 (20.9%), KMT2D (11.3%), SETD1B (8.7%), TP53 (7.0%), TNFAIP3 (6.1%), DNMT3A (5.2%), FAS (4.3%), SMARCA4 (3.5%), EPHB1 (2.6%), KSR2 (2.6%), ALOX12B (2.6%), EGFR (2.6%), DDX3X (7.0%), and IKZF3 (1.7%). When stratified by demographic variables, males and White patients demonstrated a higher frequency of mutations. This study provides a comprehensive genomic profile of T-LGLL, identifying recurrent somatic mutations and commonly affected pathways. Notably, frequent alterations were observed in the FAS-FASL signaling pathway, underscoring its potential as a target for therapeutic development.
2025-11-03 | Clinical activity, tolerability, and pharmacodynamics of ulviprubart in patients with T-cell large granular lymphocytic leukemia: Interim Results of A phase 1 trial
Abstract Background T-cell large granular lymphocytic leukemia (T-LGLL) is a rare cause of anemia and neutropenia characterized by clonal expansion of cytotoxic CD8+CD57+ T cells. It is typically treated with immunosuppressants, however, significant off-target effects can limit treatment. CD8+CD57+ T cells can also express killer cell lectin-like receptor subfamily G member 1 (KLRG1), and depletion of KLRG1+ cells may be useful for the treatment of T-LGLL. Ulviprubart is an afucosylated monoclonal antibody specific for KLRG1. Here, we detail interim results of a phase 1/2 study of 21 subjects investigating the safety, tolerability, and activity of ulviprubart. Methods In this open-label, ascending dose, adaptive clinical trial, subjects received subcutaneous injections of ulviprubart at 0.25, 0.75, 1.5, or 3 mg/kg in five cohorts. Subjects were first dosed every 8 weeks (Q8W) in cohorts 1-3 at dosages of 0.25, 0.75, and 1.5 mg/kg. Cohorts 4 and 5 were dosed every 4 weeks (Q4W) at dosages of 1.5 and 3 mg/kg respectively. PK/PD and safety were regularly assessed.Data is presented for subjects who attained and maintained Q4W dosing at 1.5mg/kg or 3mg/kg for at least 12 weeks. Amelioration of neutropenia was defined as a 4-week ANC increase ≥ 50% from baseline and amelioration of anemia was defined as a 4-week Hgb increase ≥ 1 g/dL not attributable to transfusion or growth factor. Results 21subjects were enrolled. Mean age (range) was 57 (22,87) years, 14 were female, 20 presented with neutropenia and 12 with anemia. Only 1 treatment related SAE was reported (Grade 3 infusion related reaction hours after a 3 mg/kg dose and a blood transfusion that occurred before dosing). There were no discontinuations due to adverse events. 13 subjects achieved 12 weeks of Q4W dosing. Of these, all of whom had neutropenia at baseline, 7 (53%) had improvement of neutropenia of > 50% or greater than 1000 neutrophils/dL; of the 9 with anemia at baseline, 2 (22%) had increased hemoglobin of at least 1 g/dL. Pharmacodynamic response was variable. Of the 13 subjects evaluated, an effect of at least 50% depletion of CD8+CD57+ T cells was observed in 7 (54%); of these 7 subjects, 3 had a sustained depletion of > 90% and 4 had a sustained depletion of between 50-75%. 1 subject achieved a sustained depletion of 70% of the CD8+ KLRG1+ and CD8+ CD57+ KLRG1+ T cells, but this extent of depletion was not reflected in the respective parent populations of CD8+ and CD8+CD57+ T cells. 5 subjects did not achieve any significant level of depletion. Notably, of the 5 subjects without a significant PD effect, 2 had no detectable KLRG1 expression at baseline and 1 was profoundly lymphopenic. Conclusion In this small study, Q4W dosing of ulviprubart (1.5 or 3 mg/kg) was active in depleting cytotoxic KLRG1+ T cells and was well tolerated. There was a 53% response rate for patients with neutropenia and 22% response in patients with anemia with Q4 week dosing, supporting further clinical study.
2024-11-05 | Activating STAT3 Mutations Drive CD38 Expression in T-Large Granular Lymphocytic Leukemia
The tumor-specific expression of CD38 is a crucial prognostic marker and a key therapeutic target in various hematologic malignancies. However, the regulatory mechanisms of CD38 expression in malignant cells are not well understood. This study identifies a cohort of T-cell large granular lymphocytic leukemia (T-LGLL) patients where CD38 expression correlates with STAT3 mutations. T-LGLL, a rare and incurable disease, involves the clonal proliferation of mature cytotoxic T-cells. STAT3 gain-of-function mutations (STAT3MUT), found in 40-70% of patients, result in constitutively active STAT3 proteins with pro-oncogenic properties. Our flow cytometry analysis reveals that CD38 expression in gated T-large granular lymphocytes (T-LGLs) from STAT3MUT T-LGLL patients (18/45, 40%) is significantly higher compared to STAT3 wild-type (STAT3WT) T-LGLL (n=27) and healthy donors (HD, n=10). Specifically, mutated patients showed a markedly increased percentage of CD38+ cells (STAT3MUT: 69±22%; STAT3WT: 12±15%; HD: 21±8%, p<0.001) and an elevated CD38 mean fluorescence intensity (MFI) (STAT3MUT: 839±440; STAT3WT: 179±227; HD: 289±116, p<0.001). Notably, T-LGLL patients which exhibited higher CD38 expression also experienced a severe disease progression compared to the indolent clinical course observed in CD38dim/- cases. To investigate the role of STAT3 in regulating CD38 expression, we performed chromatin immunoprecipitation (ChIP) sequencing, which revealed increased STAT3 binding at the CD38 gene locus in STAT3MUT T-LGLL patients compared to those with STAT3WT (n=12 and 7, respectively). In addition, ChIP-qPCR demonstrated an increased H3K27Acetylation, a marker of active transcription, at the CD38 promoter in STAT3MUT T-LGLL patient [STAT3MUT (n=5): 0,9±0,4; STAT3WT (n=10): 0,4±0,2; p<0.01)]. These findings were further substantiated at the transcript level, showing a significant 5-fold increase (p<0.01) of CD38 mRNA level in STAT3MUT T-LGLL patients. Our results indicate that STAT3 directly influences CD38 transcription, providing a mechanistic link between aberrant STAT3 activation and elevated CD38 expression in T-LGLL patients. To further evaluate the role of STAT3 in regulating CD38 expression, we utilized the MOTN-1 human T-LGLL cell line with STAT3WT and generated an isogenic cell line model harboring one of the most frequently observed STAT3 mutation (D661Y) found in patients. This was achieved using a CRISPR/Cas9-mediated homology-directed repair editing strategy. The resulting cell line exhibited constitutively active STAT3 and displayed a higher CD38 mRNA level and MFI compared to the WT counterpart, underscoring the impact of the STAT3 mutation on CD38 expression. Both cell lines were transduced with a firefly luciferase-GFP lentivirus for efficient in vivo tracking and then transplanted into immunodeficient Rag−/−γc−/− mouse models, representing either STAT3WT or STAT3MUT. This setup was used to assess the potential of targeting T-LGLL with the anti-CD38 mAb daratumumab. After confirming cell engraftment via bioluminescence imaging, mice were randomized into vehicle and daratumumab treatment groups. The T-LGLL cell burden resulted lower in daratumumab-treated mice compared to vehicle-treated controls, as measured by IVIS imaging. Notably, the tumor reduction in STAT3WT T-LGLL was less pronounced (1.8-fold decrease, n=4 each, p=0.23) compared to the significant reduction observed in mutant T-LGLL (2.64-fold decrease, n=4 each, p=0.04). This indicates the effectiveness of daratumumab in inhibiting tumor growth in STAT3 mutant T-LGLL model. In summary, our work provides new insight on the oncogenic role of STAT3 in regulating CD38 expression in T-LGLL and suggests that immune-targeting of CD38 could serve as a promising new therapeutic strategy for T-LGLL patients.
2024-09-07 | The emerging role of Rituximab in the treatment of large granular lymphocytic leukemia associated with rheumatoid arthritis: a single center experience.
Large Granular Lymphocytic (LGL) leukemia is a rare lymphoproliferative disorder with a peculiar association with Rheumatoid Arthritis (RA). The most common feature is neutropenia and patients can have splenomegaly, resembling Felty's Syndrome. These diseases have similar clinical and laboratory abnormalities, but the diagnosis of T-cell LGL (T-LGL) leukemia requires evidence of clonality. Even though T-LGL leukemia is indolent in most cases, inadequate treatment when it is indicated can lead to significant morbidity and mortality, mainly associated with recurrent infections. We present two clinical cases that emphasize the emerging role of Rituximab as an effective therapeutic option in patients with T-LGL and RA.
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2023-02-27 | Case Report: mRNA vaccination-mediated STAT3 overactivation with agranulocytosis and clonal T-LGL expansion.
Vaccines against SARS-CoV-2 are the most effective measure against the COVID-19 pandemic. The safety profile of mRNA vaccines in patients with rare diseases has not been assessed systematically in the clinical trials, as these patients were typically excluded. This report describes the occurrence of agranulocytosis within days following the first dose of an mRNA-1273 vaccination against COVID-19 in a previously healthy older adult. The patient was diagnosed with a suspected STAT3 wild-type T-cell large granular lymphocytic leukaemia (T-LGL). Neutropenia was successfully treated with IVIG, glucocorticoids, and G-CSF. In vitro experiments aimed at elucidating the pathways potentially causing the mRNA vaccine-associated neutropenia indicated that the mRNA, but not the adenoviral Ad26.COV2.S vector vaccine, triggered strong IL-6/STAT3 activation in vitro, resulting in excessive T-cell activation and neutrophil degranulation in the patient but not in controls. mRNA-1273 activated TLR-3 suggesting TLR mediated IL-6/STAT3 pathway activation. To complete the primary series of COVID-19 immunization, we used a single dose of Ad26.COV2.S vector vaccine without reoccurrence of neutropenia. The T-LGL clone remained stable during the follow-up of more than 12 months without ongoing therapy. Our data suggest that switching the immunization platform may be a reasonable approach in subjects with rare associated hematologic side effects due to excess STAT3-mediated stimulation following mRNA vaccination. Using in vitro testing before re-administration of a (COVID) vaccine also has relevance for other rare immune events after (mRNA) vaccination.
2022-04-06 | miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia.
T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
2022-03-16 | Isolated anemia in patients with large granular lymphocytic leukemia (LGLL).
Patients with large granular lymphocytic leukemia (LGLL) frequently present with neutropenia. When present, anemia is usually accompanied by neutropenia and/or thrombocytopenia and isolated anemia is uncommon. We evaluated a cohort of 244 LGLL patients spanning 15 years and herein report the clinicopathologic features of 34 (14%) with isolated anemia. The patients with isolated anemia showed a significantly male predominance (p = 0.001), a lower level of hemoglobulin (p < 0.0001) and higher MCV (p = 0.017) and were less likely to have rheumatoid arthritis (p = 0.023) compared to the remaining 210 patients. Of the 34 LGLL patients with isolated anemia, 13 (38%) presented with pure red cell aplasia (PRCA), markedly decreased reticulocyte count and erythroid precursors, and more transfusion-dependence when compared to non-PRCA patients. There was no other significant clinicopathologic difference between PRCA and non-PRCA patients. 32 patients were followed for a median duration of 51 months (6-199). 24 patients were treated (11/11 PRCA and 13/21 non-PRCA patients, p < 0.02). The overall response rate to first-line therapy was 83% [8/11 (72.7%) for PRCA, 12/13 (92.3%) for non-PRCA], including 14 showing complete response and 6 showing partial response with a median response duration of 48 months (12-129). Half of non-PRCA patients who were observed experienced progressive anemia. During follow-up, no patients developed neutropenia; however, 5/27 (18.5%) patients developed thrombocytopenia. No significant difference in overall survival was noted between PRCA and non-PRCA patients. In summary, this study demonstrates the unique features of LGLL with isolated anemia and underscores the importance of recognizing LGLL as a potential cause of isolated anemia, which may benefit from disease-specific treatment. LGLL patients with PRCA were more likely to require treatment but demonstrated similar clinicopathologic features, therapeutic responses, and overall survival compared to isolated anemia without PRCA, suggesting PRCA and non-PRCA of T-LGLL belong to a common disease spectrum.
2021-04-27 | Identification of a miR-146b-Fas ligand axis in the development of neutropenia in T large granular lymphocyte leukemia.
Tlarge granular lymphocyte leukemia (T-LGLL) is characterized by the expansion of several large granular lymphocyte clones, among which a subset of large granular lymphocytes showing constitutively activated STAT3, a specific CD8+/CD4- phenotype and the presence of neutropenia has been identified. Although STAT3 is an inducer of transcription of a large number of oncogenes, so far its relationship with miRNAs has not been evaluated in T-LGLL patients. Here, we investigated whether STAT3 could carry out its pathogenetic role in T-LGLL through an altered expression of miRNAs. The expression level of 756 mature miRNA was assessed on purified T large granular lymphocytes (T-LGLs) by using a TaqMan Human microRNA Array. Hierarchical Clustering Analysis of miRNA array data shows that the global miRNome clusters with CD8 T-LGLs. Remarkably, CD8 T-LGLs exhibit a selective and STAT3-dependent repression of miR-146b expression, that significantly correlated with the absolute neutrophil counts and inversely correlated with the expression of Fas ligand (FasL), that is regarded as the most relevant factor in the pathogenesis of neutropenia. Experimental evidence demonstrates that the STAT3-dependent reduction of miR-146b expression in CD8 T-LGLs occurs as a consequence of miR-146b promoter hypermethylation and results in the disruption of the HuR-mediated post-transcriptional machinery controlling FasL mRNA stabilization. Restoring miR-146b expression in CD8 T-LGLs lead to a reduction of HuR protein and, in turn, of FasL mRNA expression, thus providing mechanistic insights for the existence of a STAT3-miR146b-FasL axis and neutropenia in T-LGLL.
small molecules
2026-07-28 | Clinical Manifestations and Genetic Profile of Chinese Patients with NK-Cell Large Granular Lymphocytic Leukemia-A Single-Center Retrospective Analysis.
Natural killer cell large granular lymphocytic leukemia (NK-LGLL) is a rare and heterogenous lymphoproliferative disorder. This study retrospectively evaluated 35 consecutive Chinese patients (median age 58 years) to evaluate their unique clinical-biological profiles and treatment responses. Our Chinese population exhibited a distinct comorbidity spectrum, characterized by a lower prevalence of concurrent arthritis (2.9%) and secondary malignancies, compared with Western cohorts. At diagnosis, 31.4% of the cohort had neutropenia, 42.9% had anemia, and 31.4% had thrombocytopenia. The median large granular lymphocyte count was 3.9 × 109/L (range 0.11-114.8 × 109/L; IQR 1.9 × 109/L, 5.9 × 109/L). Immunophenotyping consistently identified as a CD3- CD56+ clone. Notably, genomic profiling via NGS revealed a STAT3 mutation rate of 14.3%. Regarding therapeutic efficacy, frontline immunosuppressive therapy with cyclophosphamide or cyclosporine was associated with favorable clinical responses (best overall response, complete remission rate 66.7% for both). Additionally, sirolimus emerged as a potentially highly effective salvage option, yielding an overall response rate of 85.7% (95%CI 42.1-99.6%) and complete remission rate of 57.1%. With an estimated 3-year overall survival rate of 85.6% (95%CI 73.3%, 99.8%), our findings suggest a generally indolent clinical course of NK-LGLL in this Chinese cohort and highlight the potential of mTOR inhibition in refractory cases, warranting further prospective investigation.
2026-07-23 | [Sustained complete remission achieved with tofacitinib in a refractory T-cell large granular lymphocytic leukemia].
Treatment of large granular lymphocytic leukemia, particularly T-cell leukemia (LGL-T), remains challenging. JAK inhibitors, although still scarcely evaluated, appear promising. An 85-year-old woman was treated for a refractory LGL-T associated with neutropenia, unclassified polyarthritis and vitiligo. During the 7-year course of the disease, she received alternatively cyclosporine, cyclophosphamide and methotrexate, associated with prednisone and/or filgrastim. During a severe relapse with agranulocytosis complicated by infectious pneumonia, no response was observed after 14 days of filgrastim. Ten days after initiation of tofacitinib, a marked increase of the neutrophil count (98G/L) occurred, associated with Sweet syndrome. Both resolved rapidly with filgrastim discontinuation. Tofacitinib allowed a rapid and complete remission of both hematological and clinical manifestations, which was maintained throughout 37 months of follow-up. This report adds to the limited evidence supporting tofacitinib in LGL-T and further highlights the potential of JAK-inhibition, particularly in refractory and systemic forms.
2026-06-06 | T-cell large granular lymphocyte leukaemia with pure red cell aplasia harbouring a somatic STAT3 P715L mutation.
T-cell large granular lymphocyte leukaemia (T-LGLL) is a chronic lymphoproliferative disorder often associated with pure red cell aplasia (PRCA). We report a unique case of a woman in her 50s presenting with PRCA secondary to T-LGLL, in which targeted next-generation sequencing identified a somatic STAT3 P715L mutation. This variant, previously described only in germline mutation in STAT3 gain-of-function syndrome, has not been reported as a somatic mutation in T-LGLL. Immunohistochemical analysis revealed constitutive STAT3 (signal transducer and activator of transcription 3) activation in clonal CD8+ T cells, suggesting a pathogenic role for the P715L mutation. The patient responded to ciclosporin therapy with gradual haematological improvement and became transfusion-independent within 6 months. This case highlights the importance of molecular profiling in T-LGLL presentations and expands the known mutational spectrum of STAT3 It also raises the possibility that non-SH2 (Src homology 2) domain STAT3 mutations may contribute to disease pathogenesis and influence treatment response in T-LGLL.
2026-04-29 | Molecular Biological Insights into Large Granular Lymphocyte Leukemia
Large granular lymphocytic leukemia (LGLL) represents a rare, indolent T-cell lymphoproliferative disorder. Clinically, it frequently manifests as cytopenia and organ infiltration. First-line immunosuppressive therapy induces clinical remission in approximately one-third to one-half of patients. Nevertheless, a significant proportion of patients experience a chronic disease course, necessitating long-term disease management. Precision medicine emerges as the pivotal future direction for this disease, with advances in molecular biology serving as the most potent driving force. In recent years, facilitated by the widespread adoption of next-generation sequencing technologies, the diagnostic and prognostic significance of gene mutations – such as those in STAT3 and STAT5B – has become increasingly elucidated within LGLL. These discoveries concurrently provide a rational foundation for exploring targeted therapeutic approaches, notably JAK inhibitors. However, the molecular landscape of LGLL remains substantially uncharted territory, warranting dedicated research efforts. This review synthesizes current progress in the molecular biology of LGLL, aiming to stimulate further investigation and offer insights for researchers in the field.
2026-03-03 | P066 | <i>STAT3</i>-mediated circular RNAs dysregulation in neutropenic T-large granular lymphocyte leukemia patients
Introduction. T-Large Granular Lymphocyte Leukemia (T-LGLL) is a rare chronic lymphoproliferative disorder with unclear pathogenesis. Clonal expansion is driven by pro-inflammatory cytokines that induce JAK/STAT stimulation. Activating STAT mutations have been identified, with STAT3 lesions being typical of CD8+ T-LGLL and distinguishing symptomatic cases, mainly for neutropenia, from indolent ones. The discovery of the STAT3-miR-146b-FasL axis in STAT3-mutated CD8+ cases has highlighted the role of non-coding RNAs (ncRNAs). This study aims to clarify the role of circular RNAs (circRNAs), a class of ncRNAs, whose involvement in T-LGLL remains unexplored.Methods. We considered RNA-sequencing (RNA-seq) data (GEO GSE228868) of 20 T-LGLL cases and 5 healthy donors (HD). CircRNA identification and analysis was carried out using the CircCompara2/edgeR pipeline. Candidate circRNAs were validated in an independent cohort (n=26) through Sanger sequencing and RT-qPCR. Patient cells were treated with IL-6 (20 ng/μL) or the STAT3 inhibitor STATTIC (ST) (3.5 μM). After 24 hours cell viability, STAT3 activation, and circRNA expression were assessed via Annexin V staining, western blot, and RT-qPCR, respectively.Results. A total of 5,948 circRNAs (p-adj<0.05) were detected through RNA-seq. Principal component analysis revealed distinct circRNA expression patterns between T-LGLL patients and HD, with 358 circRNAs differentially expressed in neutropenic STAT3-mutated patients compared to asymptomatic ones. The altered expression of 11 circRNAs was validated in an independent cohort. Of these, 5 were specifically altered in STAT3-mutated CD8+ patients: 4 were up-regulated, while circZC3H12B was down-regulated. Among upregulated circRNAs, circPVT1 and circZBTB46 were previously associated with oncogenic roles in different malignancies, whereas circZC3H12B, previously known as circX, was found highly expressed in normal lymphocytes and downexpressed in Acute Lymphoblastic Leukemia. To assess the potential link between STAT3 activation and circRNA dysregulation, cells from asymptomatic patients were stimulated ex vivo with IL-6 which is known to trigger STAT3. Protein activation, confirmed by western blot (p<0.01), modulated the 5 circRNAs to levels comparable to symptomatic cases. Consistently, experiments on cells from symptomatic patients with STAT3 hyperactivating variants treated with ST, an inhibitor of STAT3 phosphorylation (p<0.05), showed an inverse modulation of circRNAs expression compared to IL-6 treatment.Conclusions. This study reveals a T-LGLL-specific circRNA signature. neutropenic CD8+ STAT3-mutated patients showed a proper distinct circRNA profile, suggesting a role of these transcripts in disease severity and clinical manifestation. Experiments demonstrated that STAT3 activation drives circRNA dysregulation, offering new insights into T-LGLL pathogenesis. Future studies will explore circRNA function through siRNA silencing and RNA pull-down assays.
cell therapies
2026-06-23 | Auer Rod-Like Inclusions in T-cell Large Granular Lymphocytic Leukaemia.
A 71-year-old man presented with cytopenias and splenomegaly. Diagnostic workup revealed T-cell large granular lymphocytic leukemia (T-LGLL), characterized by a clonal CD8+ T-cell population with STAT3 mutation. A rare morphological finding of myeloperoxidase-negative Auer rod-like inclusions in the leukemic lymphocytes was observed, a feature seldom reported in this T-cell malignancy.
2026-05-20 | NK-large Granular Lymphocytic Leukemia
This chapter outlines the key immunophenotypic features of NK-large granular lymphocytic leukemia (NK-LGLL) and highlights the use of NK-cell receptor patterns, analyzed through flow cytometry, to establish NK-cell clonality. It also emphasizes the essential differences between NK-LGLL and its mimics, such as reactive NK-cell proliferation, NK-cell clones of uncertain significance, and aggressive NK-cell leukemia.
2026-04-17 | [A single-center study on the clinical characteristics of 15 cases of large granular lymphocytic leukemia].
This study retrospectively analyzed the clinical data of 15 patients diagnosed with large granular lymphocytic leukemia (LGLL) at the First Affiliated Hospital of Chongqing Medical University between January 2017 and December 2024. The median age was 50 years, and the main clinical manifestations included fatigue (73.3%), splenomegaly (46.7%), and lymphadenopathy (33.3%). None of the patients had autoimmune diseases. Laboratory examinations primarily demonstrated decreased hemoglobin levels (100%) and/or neutropenia (73.3%). The bone marrow smears showed an increase in lymphocyte proportion, and pure red cell aplasia was frequently observed. The typical immunophenotype was TCRαβ(+)TCRγδ(-)CD3(+)CD4(-)CD8(+)CD16(-)CD10(-)CD30(-)CD45RA(+)CD45RO(-)CD56(-)CD25(-), with monoclonal T-cell proliferation confirmed in all patients. Further, 8 patients demonstrated decreased complement C3 or C4 levels. The overall response rate of first-line immunosuppressive therapy for patients with LGLL was 85.7% (12/14) .
2026-03-31 | Central Nervous System Involvement as an Initial Manifestation of T-Cell Large Granular Lymphocyte Leukemia
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2026-02-10 | [The value of T-cell receptor gene rearrangement in the auxiliary diagnosis of T-cell large granular lymphocytic leukemia].
Objective: To explore the characteristics and auxiliary diagnostic value of T-cell receptor (TCR) gene rearrangement in T-cell abnormal clonal diseases, including T-cell large granular lymphocytic leukemia (T-LGLL) . Methods: Altogether, 103 newly diagnosed patients with T-LGLL, 18 with aplastic anemia (AA), 3 with pure red cell aplasia, 111 with systemic lupus erythematosus (SLE), and 30 healthy controls admitted at Jiangsu Province Hospital from September 2011 to November 2023 were enrolled. TCR gene rearrangement was detected by polymerase chain reaction and capillary electrophoresis, and TCRβ chain variable region (TCRVβ) subfamily and TCRβ chain constant region 1 (TRBC1) were detected by flow cytometry. The auxiliary diagnostic value of these three detection methods for T-LGLL was compared. Meanwhile, Sanger sequencing was used to detect STAT3 gene mutations in T-LGLL patients, and the mutation characteristics and clinical features of these patients were analyzed. Results: In T-LGLL patients, 57 were men and 46 were women, and the patients' median age was 61 (28-81) years. Altogether, 97.1% (100/103) of the patients were positive for TCR gene rearrangement, and TCRβ gene rearrangement showed the highest incidence (95.1%, 98/103). TCRβ gene rearrangements were further classified into TCRβ (V-J) (42.9%, 42/98), TCRβ (D-J) (15.3%, 15/98), and copositive for two TCRβ gene rearrangements (41.8%, 41/98). This was followed by TCRγ (47.6%, 49/103) and TCRδ (4.9%, 5/103) gene rearrangements. The detection rates of TCRVβ and TRBC1 were 89.5% (51/57) and 73.5% (25/34), respectively. The detection rate of TRBC1 was significantly lower than that of TCR gene rearrangement (P=0.004). The detection rates of TCR gene rearrangement in the AA, SLE, and healthy control groups were 19.0%, 6.3%, and 3.3%, respectively. Compared with healthy controls and SLE patients, the T-LGLL patients had significantly lower HGB, RBC, and ANC but significantly higher absolute lymphocyte count (ALC) (all P<0.01). Compared with the AA group, the white blood cell count, ALC, and platelet counts of the T-LGLL patients were significantly higher (all P<0.001). Compared with the AA, SLE, and healthy control groups, the T-LGLL patients were older and had a significantly higher detection rate of TCR gene rearrangement (all P<0.05). Within the T-LGLL cohort, patients with positive TCRβ (D-J) gene rearrangement had significantly lower incidence of autoimmune diseases (3.6% vs 19.1%, P=0.011) and HGB of ≥100 g/L (33.9%vs 63.8%, P=0.002), but a significantly higher incidence of B symptoms (64.3% vs 38.3%, P=0.009), than those patients without this rearrangement. Meanwhile, patients with positive TCRγ gene rearrangement had significantly higher incidence of STAT3 gene mutations (58.3% vs 30.2%, P=0.012). The median follow-up time and overall survival (OS) rate of T-LGLL patients were 43 (3-178) months and 95.1% (98/103), respectively. No significant difference in the OS was observed among the patients with different types of TCR gene clonal rearrangements (all P>0.05) . Conclusion: The detection rate of TCR gene rearrangement for T-cell clones is higher than that of TCRVβ and TRBC1. Patients with positive TCRβ (D-J) gene rearrangement have a higher incidence of B symptoms, lower incidence of autoimmune diseases, and lower HGB levels. Patients with positive TCRγ gene rearrangement are more likely to develop STAT3 gene mutation. These characteristics may be helpful in the differential diagnosis of T-LGLL.
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2026-06-17 | Observation of Hematologic Improvement with Luspatercept in Patients with Anemia from Diverse Hematologic Disorders: A Single-Center Retrospective Clinical Analysis
Background: Anemia is a common clinical condition in hematology, associated with diverse etiologies and treatment strategies, many of which have notable limitations. Luspatercept, a novel erythroid maturation agent, has shown promise in treating anemia, particularly in patients with β-thalassemia and myelodysplastic syndromes (MDS). This study aimed to evaluate the real-world hematologic effectiveness of luspatercept across various anemia subtypes. Materials and Methods: A retrospective observational study was conducted on 22 patients with anemia of different origins—MDS, post-hematopoietic stem cell transplantation (HSCT), aplastic anemia (AA), and T-cell large granular lymphocytic leukemia (T-LGLL)—who received luspatercept therapy at the 960th Hospital from June 2023 to January 2025. Hematologic improvement was assessed using the International Working Group (IWG) 2018 criteria for erythroid response (HI-E). Pre- and post-treatment changes in hemoglobin (Hb), reticulocyte percentage (RET %), and absolute reticulocyte count (RET #) were analyzed using the Wilcoxon Signed-Rank Test. Multivariate regression was employed to control for age, gender, and disease severity. Statistical significance was set at P ≤ 0.05, and all analyses were performed using SPSS version 27.0. Results: Among the 22 patients, 10 (45.5%) had MDS (5 low-risk, 5 intermediate-to-high-risk), 6 (27.3%) post-HSCT anemia, 4 (18.2%) AA, and 2 (9%) T-LGLL. A total of 16 patients (72.7%) achieved a clinically meaningful erythroid response. Seven (43.8%) of these remained transfusion-independent until the last follow-up, with a median duration of 19.5 weeks (range: 8.6–47). Median time to initial response was 3.86 weeks (range: 0.57–25.57). Significant increases were observed in Hb (P < 0.001) and RET # (P = 0.001), while the increase in RET % did not reach statistical significance (P = 0.088). These findings support the efficacy of luspatercept in promoting erythropoiesis and improving anemia in a heterogeneous patient population. Conclusion: Luspatercept demonstrated significant hematologic improvement, particularly in hemoglobin levels, in patients with anemia from various hematologic disorders. These results support its broader therapeutic potential. Future multicenter, prospective studies are warranted to validate its role in treating other forms of anemia.
2023-10-23 | Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia.
T-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes that can result in severe neutropenia, anemia, and bone marrow failure. Strong evidence from patients and mouse models demonstrate the critical role of interleukin-15 (IL-15) in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other γc cytokines to their cellular receptor complex, which has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in preclinical studies. We conducted a phase 1/2 trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) and required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based on response criteria from the Eastern Cooperative Oncology Group 5998 T-LGLL trial. BNZ-1 demonstrated clinical partial responses in 20% of patients with T-LGLL with minimal toxicity and the maximum tolerated dose was not reached. Furthermore, T-LGL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day 2, including in clinical nonresponders, with changes that remained statistically different from baseline throughout treatment (P < .005). We report first-in-human proof that T-LGL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in patients with T-LGLL shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. This trial was registered at www.clinicaltrials.gov as #NCT03239392.
2019-08-14 | [Successful treatment of pure red cell aplasia with cyclosporin in a patient with T-cell large granular lymphocytic leukemia harboring the STAT3 D661V mutation].
T-cell large granular lymphocyte (T-LGL) leukemia is a chronic T-cell monoclonal disease that is occasionally associated with pure red cell aplasia (PRCA). A 71-year-old previously healthy man complained of physical fatigue and exhibited anemia (hemoglobin, 10.5 g/dl) with lymphocytosis (76%) showing LGL. The LGL cells expressed CD3, CD7, CD8, and T-cell receptor (TCR) -α/β. TCR-β/γ gene rearrangement was positive. He was thus diagnosed with CD8＋ T-LGL leukemia. Anemia progressed with low reticulocyte count (0.11%), and the patient became blood transfusion-dependent, but no distinct abnormality caused the anemia. Bone marrow aspiration revealed an increase in lymphocytes (33.6%) and a decrease in erythroblasts (M/E ratio, 6.1). He was thus diagnosed with T-LGL-associated PRCA. Oral cyclosporin A administration resulted in prompt improvement of anemia, suggesting its high sensitivity. Whole-exome sequencing of his peripheral blood DNA revealed somatic mutations in 33 genes, including the STAT3 gene, implying their roles in T-LGL leukemia.
2018-10-23 | IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability
Interleukin-15 (IL-15) and IL-2 drive T-cell malignancies including T-cell large granular lymphocyte leukemia (T-LGLL) and HTLV-1 driven adult T-cell leukemia (ATL). Both cytokines share common γ-chain receptors and downstream signaling pathways. T-LGLL is characterized by clonal expansion of cytotoxic T cells and is associated with abnormal JAK/STAT signaling. ATL is an aggressive CD4+ T-cell neoplasm associated with HTLV-1. T-LGLL and ATL share dependence on IL-2 and IL-15 for survival and both diseases lack effective therapies. BNZ-1 is a pegylated peptide designed to specifically bind the γc receptor to selectively block IL-2, IL-15, and IL-9 signaling. We hypothesized that treatment with BNZ-1 would reduce cytokine-mediated proliferation and viability. Our results demonstrated that in vitro treatment of a T-LGLL cell line and ex vivo treatment of T-LGLL patient cells with BNZ-1 inhibited cytokine-mediated viability. Furthermore, BNZ-1 blocked downstream signaling and increased apoptosis. These results were mirrored in an ATL cell line and in ex vivo ATL patient cells. Lastly, BNZ-1 drastically reduced leukemic burden in an IL-15-driven human ATL mouse xenograft model. Thus, BNZ-1 shows great promise as a novel therapy for T-LGLL, ATL, and other IL-2 or IL-15 driven hematopoietic malignancies.
2016-01-01 | The case of T-cell large granular lyphocyte leukemia presented as transfusion dependent anemia with sustained response to cyclosporine a therapy: Case report
Case report. A 41-year-old man presented with anemia, lymphocytosis and splenomegaly. T-cell large granular lymphocyte leukemia was diagnosed based on lymphocytosis of T-cell large granular lymphocytes, characteristic immunophenotype (CD3+, CD8+, CD16+, CD57+) of the lymphocytes and clonally rearranged T-cell receptor genes. Therapy indication was transfusion-dependent anemia. Initial cyclosporine therapy and low-dose oral methotrexate failed to control anemia and lymphocytosis. Yet, a complete clinical and hematological response (without molecular remission) was achieved and sustained when cyclosporine was reintroduced into the therapy. Conclusion. Our case confirms that cyclosporine therapy is effective in treating T-cell large granular lymphocyte leukemia and suggests that indefinite treatment may not be needed to maintain the response.
antibodies
2026-08-06 | Multilineage lymphoid clonal hematopoiesis: a cross-sectional, correlative analysis of plasma cell dyscrasias and large granular lymphocytic leukemia.
Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.
2026-01-03 | Mutational Spectrum of T-Cell Large Granular Lymphocytic Leukemia: Insights From the AACR Project GENIE Consortium.
T-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder of cytotoxic T cells in the peripheral blood, bone marrow, and spleen. This analysis was conducted to characterize genomic alterations and highlight potential therapeutic targets, with the goal of refining the molecular landscape of T-LGLL by emphasizing population-specific biomarkers. This study utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to identify common gene mutations. Using the AACR GENIE database, a retrospective analysis of T-cell large granular lymphocyte leukemia (T-LGLL) samples was performed. The data was evaluated by extracting patient demographics and excluding synonymous mutations from consideration. Statistical significance was assessed using chi-squared tests and computational analyses in RStudio (R Foundation for Statistical Computing, Boston, MA, USA). Somatic mutations and chromosomal copy number variations were evaluated, with statistical significance defined as p=0.001. Frequently observed somatic mutations included STAT3 (41.7%), STAT2 (20.9%), KMT2D (11.3%), SETD1B (8.7%), TP53 (7.0%), TNFAIP3 (6.1%), DNMT3A (5.2%), FAS (4.3%), SMARCA4 (3.5%), EPHB1 (2.6%), KSR2 (2.6%), ALOX12B (2.6%), EGFR (2.6%), DDX3X (7.0%), and IKZF3 (1.7%). When stratified by demographic variables, males and White patients demonstrated a higher frequency of mutations. This study provides a comprehensive genomic profile of T-LGLL, identifying recurrent somatic mutations and commonly affected pathways. Notably, frequent alterations were observed in the FAS-FASL signaling pathway, underscoring its potential as a target for therapeutic development.
2025-11-03 | Clinical activity, tolerability, and pharmacodynamics of ulviprubart in patients with T-cell large granular lymphocytic leukemia: Interim Results of A phase 1 trial
Abstract Background T-cell large granular lymphocytic leukemia (T-LGLL) is a rare cause of anemia and neutropenia characterized by clonal expansion of cytotoxic CD8+CD57+ T cells. It is typically treated with immunosuppressants, however, significant off-target effects can limit treatment. CD8+CD57+ T cells can also express killer cell lectin-like receptor subfamily G member 1 (KLRG1), and depletion of KLRG1+ cells may be useful for the treatment of T-LGLL. Ulviprubart is an afucosylated monoclonal antibody specific for KLRG1. Here, we detail interim results of a phase 1/2 study of 21 subjects investigating the safety, tolerability, and activity of ulviprubart. Methods In this open-label, ascending dose, adaptive clinical trial, subjects received subcutaneous injections of ulviprubart at 0.25, 0.75, 1.5, or 3 mg/kg in five cohorts. Subjects were first dosed every 8 weeks (Q8W) in cohorts 1-3 at dosages of 0.25, 0.75, and 1.5 mg/kg. Cohorts 4 and 5 were dosed every 4 weeks (Q4W) at dosages of 1.5 and 3 mg/kg respectively. PK/PD and safety were regularly assessed.Data is presented for subjects who attained and maintained Q4W dosing at 1.5mg/kg or 3mg/kg for at least 12 weeks. Amelioration of neutropenia was defined as a 4-week ANC increase ≥ 50% from baseline and amelioration of anemia was defined as a 4-week Hgb increase ≥ 1 g/dL not attributable to transfusion or growth factor. Results 21subjects were enrolled. Mean age (range) was 57 (22,87) years, 14 were female, 20 presented with neutropenia and 12 with anemia. Only 1 treatment related SAE was reported (Grade 3 infusion related reaction hours after a 3 mg/kg dose and a blood transfusion that occurred before dosing). There were no discontinuations due to adverse events. 13 subjects achieved 12 weeks of Q4W dosing. Of these, all of whom had neutropenia at baseline, 7 (53%) had improvement of neutropenia of > 50% or greater than 1000 neutrophils/dL; of the 9 with anemia at baseline, 2 (22%) had increased hemoglobin of at least 1 g/dL. Pharmacodynamic response was variable. Of the 13 subjects evaluated, an effect of at least 50% depletion of CD8+CD57+ T cells was observed in 7 (54%); of these 7 subjects, 3 had a sustained depletion of > 90% and 4 had a sustained depletion of between 50-75%. 1 subject achieved a sustained depletion of 70% of the CD8+ KLRG1+ and CD8+ CD57+ KLRG1+ T cells, but this extent of depletion was not reflected in the respective parent populations of CD8+ and CD8+CD57+ T cells. 5 subjects did not achieve any significant level of depletion. Notably, of the 5 subjects without a significant PD effect, 2 had no detectable KLRG1 expression at baseline and 1 was profoundly lymphopenic. Conclusion In this small study, Q4W dosing of ulviprubart (1.5 or 3 mg/kg) was active in depleting cytotoxic KLRG1+ T cells and was well tolerated. There was a 53% response rate for patients with neutropenia and 22% response in patients with anemia with Q4 week dosing, supporting further clinical study.
2024-11-05 | Activating STAT3 Mutations Drive CD38 Expression in T-Large Granular Lymphocytic Leukemia
The tumor-specific expression of CD38 is a crucial prognostic marker and a key therapeutic target in various hematologic malignancies. However, the regulatory mechanisms of CD38 expression in malignant cells are not well understood. This study identifies a cohort of T-cell large granular lymphocytic leukemia (T-LGLL) patients where CD38 expression correlates with STAT3 mutations. T-LGLL, a rare and incurable disease, involves the clonal proliferation of mature cytotoxic T-cells. STAT3 gain-of-function mutations (STAT3MUT), found in 40-70% of patients, result in constitutively active STAT3 proteins with pro-oncogenic properties. Our flow cytometry analysis reveals that CD38 expression in gated T-large granular lymphocytes (T-LGLs) from STAT3MUT T-LGLL patients (18/45, 40%) is significantly higher compared to STAT3 wild-type (STAT3WT) T-LGLL (n=27) and healthy donors (HD, n=10). Specifically, mutated patients showed a markedly increased percentage of CD38+ cells (STAT3MUT: 69±22%; STAT3WT: 12±15%; HD: 21±8%, p<0.001) and an elevated CD38 mean fluorescence intensity (MFI) (STAT3MUT: 839±440; STAT3WT: 179±227; HD: 289±116, p<0.001). Notably, T-LGLL patients which exhibited higher CD38 expression also experienced a severe disease progression compared to the indolent clinical course observed in CD38dim/- cases. To investigate the role of STAT3 in regulating CD38 expression, we performed chromatin immunoprecipitation (ChIP) sequencing, which revealed increased STAT3 binding at the CD38 gene locus in STAT3MUT T-LGLL patients compared to those with STAT3WT (n=12 and 7, respectively). In addition, ChIP-qPCR demonstrated an increased H3K27Acetylation, a marker of active transcription, at the CD38 promoter in STAT3MUT T-LGLL patient [STAT3MUT (n=5): 0,9±0,4; STAT3WT (n=10): 0,4±0,2; p<0.01)]. These findings were further substantiated at the transcript level, showing a significant 5-fold increase (p<0.01) of CD38 mRNA level in STAT3MUT T-LGLL patients. Our results indicate that STAT3 directly influences CD38 transcription, providing a mechanistic link between aberrant STAT3 activation and elevated CD38 expression in T-LGLL patients. To further evaluate the role of STAT3 in regulating CD38 expression, we utilized the MOTN-1 human T-LGLL cell line with STAT3WT and generated an isogenic cell line model harboring one of the most frequently observed STAT3 mutation (D661Y) found in patients. This was achieved using a CRISPR/Cas9-mediated homology-directed repair editing strategy. The resulting cell line exhibited constitutively active STAT3 and displayed a higher CD38 mRNA level and MFI compared to the WT counterpart, underscoring the impact of the STAT3 mutation on CD38 expression. Both cell lines were transduced with a firefly luciferase-GFP lentivirus for efficient in vivo tracking and then transplanted into immunodeficient Rag−/−γc−/− mouse models, representing either STAT3WT or STAT3MUT. This setup was used to assess the potential of targeting T-LGLL with the anti-CD38 mAb daratumumab. After confirming cell engraftment via bioluminescence imaging, mice were randomized into vehicle and daratumumab treatment groups. The T-LGLL cell burden resulted lower in daratumumab-treated mice compared to vehicle-treated controls, as measured by IVIS imaging. Notably, the tumor reduction in STAT3WT T-LGLL was less pronounced (1.8-fold decrease, n=4 each, p=0.23) compared to the significant reduction observed in mutant T-LGLL (2.64-fold decrease, n=4 each, p=0.04). This indicates the effectiveness of daratumumab in inhibiting tumor growth in STAT3 mutant T-LGLL model. In summary, our work provides new insight on the oncogenic role of STAT3 in regulating CD38 expression in T-LGLL and suggests that immune-targeting of CD38 could serve as a promising new therapeutic strategy for T-LGLL patients.
2024-09-07 | The emerging role of Rituximab in the treatment of large granular lymphocytic leukemia associated with rheumatoid arthritis: a single center experience.
Large Granular Lymphocytic (LGL) leukemia is a rare lymphoproliferative disorder with a peculiar association with Rheumatoid Arthritis (RA). The most common feature is neutropenia and patients can have splenomegaly, resembling Felty's Syndrome. These diseases have similar clinical and laboratory abnormalities, but the diagnosis of T-cell LGL (T-LGL) leukemia requires evidence of clonality. Even though T-LGL leukemia is indolent in most cases, inadequate treatment when it is indicated can lead to significant morbidity and mortality, mainly associated with recurrent infections. We present two clinical cases that emphasize the emerging role of Rituximab as an effective therapeutic option in patients with T-LGL and RA.
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2023-02-27 | Case Report: mRNA vaccination-mediated STAT3 overactivation with agranulocytosis and clonal T-LGL expansion.
Vaccines against SARS-CoV-2 are the most effective measure against the COVID-19 pandemic. The safety profile of mRNA vaccines in patients with rare diseases has not been assessed systematically in the clinical trials, as these patients were typically excluded. This report describes the occurrence of agranulocytosis within days following the first dose of an mRNA-1273 vaccination against COVID-19 in a previously healthy older adult. The patient was diagnosed with a suspected STAT3 wild-type T-cell large granular lymphocytic leukaemia (T-LGL). Neutropenia was successfully treated with IVIG, glucocorticoids, and G-CSF. In vitro experiments aimed at elucidating the pathways potentially causing the mRNA vaccine-associated neutropenia indicated that the mRNA, but not the adenoviral Ad26.COV2.S vector vaccine, triggered strong IL-6/STAT3 activation in vitro, resulting in excessive T-cell activation and neutrophil degranulation in the patient but not in controls. mRNA-1273 activated TLR-3 suggesting TLR mediated IL-6/STAT3 pathway activation. To complete the primary series of COVID-19 immunization, we used a single dose of Ad26.COV2.S vector vaccine without reoccurrence of neutropenia. The T-LGL clone remained stable during the follow-up of more than 12 months without ongoing therapy. Our data suggest that switching the immunization platform may be a reasonable approach in subjects with rare associated hematologic side effects due to excess STAT3-mediated stimulation following mRNA vaccination. Using in vitro testing before re-administration of a (COVID) vaccine also has relevance for other rare immune events after (mRNA) vaccination.
2022-04-06 | miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia.
T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
2022-03-16 | Isolated anemia in patients with large granular lymphocytic leukemia (LGLL).
Patients with large granular lymphocytic leukemia (LGLL) frequently present with neutropenia. When present, anemia is usually accompanied by neutropenia and/or thrombocytopenia and isolated anemia is uncommon. We evaluated a cohort of 244 LGLL patients spanning 15 years and herein report the clinicopathologic features of 34 (14%) with isolated anemia. The patients with isolated anemia showed a significantly male predominance (p = 0.001), a lower level of hemoglobulin (p < 0.0001) and higher MCV (p = 0.017) and were less likely to have rheumatoid arthritis (p = 0.023) compared to the remaining 210 patients. Of the 34 LGLL patients with isolated anemia, 13 (38%) presented with pure red cell aplasia (PRCA), markedly decreased reticulocyte count and erythroid precursors, and more transfusion-dependence when compared to non-PRCA patients. There was no other significant clinicopathologic difference between PRCA and non-PRCA patients. 32 patients were followed for a median duration of 51 months (6-199). 24 patients were treated (11/11 PRCA and 13/21 non-PRCA patients, p < 0.02). The overall response rate to first-line therapy was 83% [8/11 (72.7%) for PRCA, 12/13 (92.3%) for non-PRCA], including 14 showing complete response and 6 showing partial response with a median response duration of 48 months (12-129). Half of non-PRCA patients who were observed experienced progressive anemia. During follow-up, no patients developed neutropenia; however, 5/27 (18.5%) patients developed thrombocytopenia. No significant difference in overall survival was noted between PRCA and non-PRCA patients. In summary, this study demonstrates the unique features of LGLL with isolated anemia and underscores the importance of recognizing LGLL as a potential cause of isolated anemia, which may benefit from disease-specific treatment. LGLL patients with PRCA were more likely to require treatment but demonstrated similar clinicopathologic features, therapeutic responses, and overall survival compared to isolated anemia without PRCA, suggesting PRCA and non-PRCA of T-LGLL belong to a common disease spectrum.
2021-04-27 | Identification of a miR-146b-Fas ligand axis in the development of neutropenia in T large granular lymphocyte leukemia.
Tlarge granular lymphocyte leukemia (T-LGLL) is characterized by the expansion of several large granular lymphocyte clones, among which a subset of large granular lymphocytes showing constitutively activated STAT3, a specific CD8+/CD4- phenotype and the presence of neutropenia has been identified. Although STAT3 is an inducer of transcription of a large number of oncogenes, so far its relationship with miRNAs has not been evaluated in T-LGLL patients. Here, we investigated whether STAT3 could carry out its pathogenetic role in T-LGLL through an altered expression of miRNAs. The expression level of 756 mature miRNA was assessed on purified T large granular lymphocytes (T-LGLs) by using a TaqMan Human microRNA Array. Hierarchical Clustering Analysis of miRNA array data shows that the global miRNome clusters with CD8 T-LGLs. Remarkably, CD8 T-LGLs exhibit a selective and STAT3-dependent repression of miR-146b expression, that significantly correlated with the absolute neutrophil counts and inversely correlated with the expression of Fas ligand (FasL), that is regarded as the most relevant factor in the pathogenesis of neutropenia. Experimental evidence demonstrates that the STAT3-dependent reduction of miR-146b expression in CD8 T-LGLs occurs as a consequence of miR-146b promoter hypermethylation and results in the disruption of the HuR-mediated post-transcriptional machinery controlling FasL mRNA stabilization. Restoring miR-146b expression in CD8 T-LGLs lead to a reduction of HuR protein and, in turn, of FasL mRNA expression, thus providing mechanistic insights for the existence of a STAT3-miR146b-FasL axis and neutropenia in T-LGLL.
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Drug Discovery Landscape
2 orphan drug designations for Large granular lymphocyte leukemia.
2 orphan drug designations for Large granular lymphocyte leukemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Dibotatug | antibodies | EMA | 2026-03-25 | — | FGK Representative Service GmbH |
human anti-CD94 IgG1 monoclonal antibody (non-fucosylated) | antibodies | FDA | 2023-03-23 | — | Dren Bio, Inc |
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